U.S. Pat. No. 4,374,829 discloses the compound enalapril maleate, which is a drug useful to treat hypertension. This patent also discusses methods of formulating drugs into pharmaceutical compositions such as tablets and capsules, but discloses no example of a tablet or capsule containing specifically enalapril maleate.
In order to manufacture pharmaceutical tablets, it is necessary to mix the active ingredient with inactive ingredients which may serve as binders, fillers, disintegrating agents, lubricants, and colorants or have other purposes. Inactive ingredients are also known as "excipients".
The final mixture of active ingredient and excipients is made into tablets on a tablet press. The processes of preparing the mixture and making tablets are well known to those skilled in the art of pharmaceutical formulation.
One of the requirements for an acceptable pharmaceutical composition is that it must be stable, so as not to exhibit substantial decomposition of the active ingredient during the time between manufacture of the composition and use by the patient. Surprisingly, it has been found that enalapril maleate is not compatible with most of the usual excipients, including most of those mentioned in U.S. Pat. No. 4,374,829. Decomposition of enalapril maleate is accelerated by most of these excipients, thus making it very difficult to formulate a stable tablet containing enalapril maleate.
The difficulty of formulating a stable tablet containing enalapril maleate is confirmed by European patent application number 92119896.6. That application discloses that a stable formulation can be made by suspending enalapril maleate in water, and adding an alkaline sodium compound, whereupon an acid-base reaction occurs to convert the enalapril maleate into enalapril sodium salt (hereinafter referred to as "enalapril sodium") plus maleic acid sodium salt, thereby forming a clear solution. Other excipients are then added the mixture is dried, and the dry powder processed into tablets. Stability data contained in this patent application demonstrates that the final composition containing enalapril sodium mixed with maleic acid sodium salt and other ingredients is more stable than a similar composition containing enalapril maleate.
However, the formulations of European application 92119896.6 have the disadvantage of requiring the step of suspending the enalapril maleate in water, adding the alkaline sodium compound, and mixing until the acid-base reaction is complete.
This requires the use of more equipment than would otherwise be needed for the manufacture of tablets. Also, because the enalapril sodium is in aqueous solution during the process, significant hydrolysis can occur by which some enalaprilat is formed, thus reducing the purity of the product.
U.S. patent application Ser. No. 08/276,678 discloses that stable tablets comprising enalapril maleate can be made if excipients are restricted to certain those which do not to cause decomposition. However, this approach limits the excipients that can be used, making it difficult to produce tablets exhibiting good hardness.
In light of the foregoing, the object of the invention is to enable production of tablets through a process whereby enalapril maleate is convened to the more stable sodium salt without requiring the steps of suspending the enalapril maleate in water, adding the alkaline sodium compound, and mixing until the reaction is complete and a clear solution is formed.